Combination chemotherapy of docetaxel and UFT against hormone refractory prostate cancer

Docetaxel-based chemotherapy has been shown to be effective and well tolerated by Japanese patients with metastatic hormone-refractory prostate cancer (HRPC). This study was undertaken to assess the feasibility of docetaxel in combination with UFT (a combination of tegafur and uracil) in Japanese patients with HRPC. Ten patients aged 60-86 years with HRPC, who were pre-treated with hormonal therapy and expected to have more than 3 month survival and without major organ dysfunction, were included in this study. Treatment consisted of docetaxel 70 mg/m2 every 3 weeks plus UFT 260 mg/m2 /day. The primary end point was prostate-specific antigen (PSA) response, and the secondary end points included progression-free survival and toxicity. Nine patients were evaluable for efficacy and toxicity. The PSA response rate was 50% (1 CR and 4 PR). The most common non-hematological adverse events (of any grade) possibly related to treatment were neutropenia and anorexia. Grade 3/4 neutropenia and anorexia occurred in 50 and 20% of patients, respectively. The combination of docetaxel and UFT was feasible and active in Japanese patients with HRPC, with a manageable adverse-event profile similar to that observed in lung cancer chemotherapy.     

Combination chemotherapy with docetaxel, estramustine and suramin for hormone refractory prostate cancer

PURPOSE: To investigate more effective chemotherapy against hormone refractory prostate cancer (HRPC) with the combination of estramustine (EM), docetaxel, and suramin. PATIENTS AND METHODS: A total of 42 patients with symptomatic, progressive HRPC were included in this study. We evaluated the activity of the following schedule: EM 10 mg/kg orally daily on Days 1 to 21 every 28 days, docetaxel 70 mg/m(2) IV on Day 2 every 28 days and a total doses of 2150 mg of suramin in every cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: Median follow-up was 23.4 months. A median of 8.8 consecutive cycles was administered per patient. In the 25 patients with lymphadenopathy, there were three (12%) complete and 18 (72%) partial responses for a measurable disease response rate of 84%. Levels of prostatic specific antigen (PSA) decreased by greater than 50% in 100% of patients and by greater than 90% in 76.2%. The median time to progression was 57 weeks and median overall survival was 132 weeks. A decline in PSA of > or =50% lasting > or =30 days was significantly associated with a prolonged median time to progression and median overall survival. Tumor volume reduction and/or antitumor treatment effects were observed in 88% of patients. A significant decrease in mean pain score from 7.8 (range, 6-10) to 2.2 (range, 0-4) (P < 0.001) was achieved in 78%. Of patients with bone metastasis, 30.5% demonstrated a partial response. The mean Eastern Cooperative Oncology Group (ECOG) performance score improved from 2.8 to 1.5 at the end of treatment period. There was no therapy-related death. The predominant toxicities were Grade 3 or 4 leukopenia in 33.3%, anemia in 21%, thrombocytopenia in 21.4%, cardiac ischemia in 4.7%, and rash in 4.7%. CONCLUSION: The combination of docetaxel, EM, and suramin is a highly effective regimen for HRPC. Although hematologic and gastrointestinal toxicities were modest, these were easily managed medically.     

Combination chemotherapy with weekly docetaxel and estramustine for hormone refractory prostate cancer in Japanese patients

Abstract:   The aim is to evaluate the efficacy and toxicity of weekly docetaxel and estramustine for Japanese men with hormone refractory prostate cancer who were treated at a single institution. Twenty eligible patients had histologically proven adenocarcinoma of the prostate with metastases that were progressing despite complete androgen blockade and antiandrogen withdrawal. All of the patients received docetaxel 30 mg/m² weekly (days 1, 8, 15, 22, 29, and 36). After a two week break, the treatment schedule was repeated. Patients were scheduled to receive daily oral estramustine 560 mg/day throughout the protocol. In the serum prostate specific antigen (PSA) response, three (15%) patients achieved a complete response, and 8 (40%) acheived a partial response. Overall survival and time to progression were 13.4 months and 6.4 months, respectively, however sixty-seven percent of the patients had to discontinue treatment because of toxicity. The high toxicity of this protocol suggests that the regimen and/or the timing should be altered for Japanese patients.     

Combination therapy with estramustine and docetaxel for hormone refractory prostate cancer

Six patients with hormone refractory prostate cancer were orally administered 560 mg of Estramustine daily in 2 equally divided doses for four or five days. In addition 70 mg/m2 of Docetaxel was infused through intravenous drip from day 1, decreasing to 40-60 mg/m2 if any side effects such as bone marrow depression were observed. One cycle was three weeks in hospital and one month after discharge. Patients were treated until progression or the development of treatment-limiting toxicity. In five of the six patients (83.3%), serum prostate specific antigen (PSA) was decreased by more than 50%. Currently, this therapy is ongoing in four outpatients. A side effect of leucopenia (grade 2 or 3) was observed in all patients. Granulocyte-colony stimulating factor (G-CSF) formulation was given as treatment. One case was withdrawn due to loss of appetite after one cycle. This therapy is considered to be effective against hormone refractory prostate cancer. However, further examination is needed about dosage and dosing regimen of Estramustine and Docetaxel.     

Scleroderma-like skin sclerosis induced by docetaxel chemotherapy for hormone refractory prostate cancer: a case report

We report the first case of scleroderma-like skin sclerosis induced by docetaxel chemotherapy for prostate cancer in Japan. A 67-year-old man underwent radical prostatectomy for cT3aN0M0 prostate cancer in 2003. Thereafter PSA recurrence developed and antiandrogen deprivation therapy was used. However, we diagnosed this case as hormone refractory prostate cancer and began docetaxel chemotherapy in October 2008. There were no nonhematological adverse events through two courses of treatment. He presented to dermatology due to pain and swelling of both upper arms on the second day of the third course. However, when treated with a cooling method, swelling of the upper arms became worse and CPK rose to 1,921 IU/I on the eighth day. We administered a steroid ointment and an antibiotic due to suspicion of thrombophlebitis. Nevertheless, CPK rose to 2,791 IU/I and a skin biopsy was done. In consequence, scleroderma-like skin sclerosis induced by docetaxel chemotherapy was diagnosed. Swelling appeared in both lower limbs and the pain got worse on the 17th day. Therefore docetaxel chemotherapy was discontinued and prednisolone was increased to 30 mg/day, in addition to beginning codeine use for the pain. Thereafter, the painful sclerosis was ameliorated.     

KIFC1 induces resistance to docetaxel and is associated with survival of patients with prostate cancer

Objectives

Prostate cancer (PCa) is a common malignancy worldwide. Docetaxel has been an important treatment option for patients with metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients with CRPC treated with docetaxel eventually become refractory. In the present study, we analyzed the expression and distribution of kinesin family member C1 (KIFC1) in human PCa by immunohistochemistry and examined the effect of inhibiting KIFC1 expression on docetaxel resistance.

Circulating chromogranin a and hormone refractory prostate cancer chemotherapy

PURPOSE: Neuroendocrine differentiation is a frequent pattern in prostate adenocarcinoma. CgA seems to be a useful indicator of neuroendocrine differentiation in patients with HRPC. We evaluated the clinical interest of circulating CgA in HRPC. MATERIALS AND METHODS: Serum CgA was assessed by immunoradiometric assay in 39 patients with HRPC treated with paclitaxel and carboplatin or mitoxantrone. Baseline CgA and its variation during chemotherapy were studied. RESULTS: Increased serum CgA was observed in 45% of patients. Previous local radiotherapy and the duration of hormonal therapy were independent factors that influenced CgA. There was no correlation between CgA and prostate specific antigen. Increased serum CgA showed positive predictive significance but no prognostic value. The chemotherapy response correlated with a CgA decrease of greater than 25%. CONCLUSIONS: The current study suggests that CgA assessment facilitates patient selection by predicting the chemotherapy response and providing complementary information to follow the chemotherapy response.     

Current status of cytotoxic chemotherapy in hormone refractory prostate cancer

Adenocarcinoma of the prostate is the most prevalent neoplastic disease in men and continues to be a major cause of morbidity and mortality. Death from prostate cancer is associated with objective and biochemical progression following hormonal manipulations often described as hormone refractory prostate cancer (HRPCA). Therapy for HRPCA is primarily palliative and therapeutic efficacy has to be balanced against potential treatment-related side effects. Therapeutic efficacy may be assessed by evaluating the percentage of patients obtaining a PSA decline of > 50%, evaluating the response of bidimensionally measurable disease or by improvements in quality of life assessments. The most effective cytotoxic therapies at the present time seem to be combinations of estramustine phosphate with taxanes and etoposide. Regimes employing ketoconazole with estramustine, vinblastine or bisphosphonates seem to be worthy of further evaluation. Mitoxantrone has an impressive palliative effect in patients, particularly when combined with hydrocortisone. Oral chemotherapeutic regimens with a combination of estramustine phosphate, cyclophosphamide and prednisone appear to offer a less toxic alternative. For the future we need prospective randomized clinical phase-III studies, prognosticators identifying patients as being at high or low risk who might benefit from different therapeutic approaches and generally binding eligibility and response guidelines in order to be able to compare trials of different therapeutic approaches.     

Docetaxel-based chemotherapy with zoledronic acid and prednisone in hormone refractory prostate cancer: Factors predicting response and survival

Objectives:   To evaluate the efficacy of docetaxel/prednisone and zoledronic acid in hormone refractory prostate cancer (HRPC) patients and to analyze prognostic factors predicting overall survival.
Methods:   Forty-four HRPC patients were given docetaxel (75 mg/m²), prednisone and zoledronic acid (4 mg) every three weeks. Overall and progression-free survival curves were calculated. Using the log–rank test, variables predicting overall survival (age, Gleason score, baseline prostate-specific antigen [PSA], percentage PSA decline, nadir PSA, number of chemotherapy cycles) were calculated.
Results:   Median age was 66 years and mean PSA 171.25 ng/mL. The average number of given cycles was 6.3. A good PSA response (>50% decline) was observed in 26/44 cases (59.1%). A total of 17/44 (38.6%) patients expired with a median overall survival of 62.4 weeks. Patients with a Gleason score less than 7, who received more than four cycles and with a more-than-50% decline in PSA had significantly better survival. Variables like age, baseline PSA and nadir PSA did not significantly affect survival.
Conclusion:   The combination of docetaxel/zoledronic/prednisone is safe and effective in the management of HRPC. Patients with a Gleason score <7, PSA decline >50% and those who receive more than four cycles have significantly better survival.     

Single-agent chemotherapy with docetaxel significantly reduces PSA levels in patients with high-grade localized prostate cancers

OBJECTIVE: Chemotherapy has been shown to be effective in the management of prostate cancer in patients with androgen-independent metastatic disease, however, a survival benefit has not been demonstrated yet. Docetaxel alone or in combination with estramustine has been shown to exhibit a high level of activity in the treatment of hormone-refractory prostate cancer. To date there are only few reports on chemotherapy for localized prostate cancer. METHODS: The efficacy and safety of neoadjuvant chemotherapy with docetaxel as a single agent given prior to radical retropubic prostatectomy (RRP) has been evaluated in 5 patients presenting with Gleason score 8 prostate cancers at biopsy. RESULTS: The mean reduction in prostate-specific antigen levels in the 5 patients was 66.5% (range 47.6-94.0%). Histology after RRP yielded pT2N0MxR0 prostate cancers in all subjects. Testosterone and secretoneurin levels were not significantly affected by docetaxel monotherapy. CONCLUSIONS: Although the use of neoadjuvant chemotherapy prior to RRP is still experimental, the dramatic prostate-specific antigen decrease during chemotherapy and the pathologic findings after radical prostatectomy are encouraging. Studies including larger number of patients will have to confirm the present results.     

Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer

Prostate cancer is a leading cause of cancer death, frequently associated with widespread bone metastases. We report two cases of hypocalcemia following the first dose of denosumab in metastatic hormone refractory prostate cancer, the first case requiring 26 days of intravenous calcium therapy. This is the first report of prolonged hypocalcemia following denosumab in a patient with normal renal function.     

Combination chemotherapy with paclitaxel,estramustine and carboplatin for hormone refractory prostate cancer

PURPOSE: The activity of estramustine phosphate is synergistic with paclitaxel against hormone refractory prostate cancer. Moreover, the single agent activity of carboplatin has demonstrated a 17% response rate in measurable disease. Therefore, we conducted a prospective trial to establish more effective chemotherapy consisting of paclitaxel, estramustine phosphate and carboplatin for hormone refractory prostate cancer. MATERIALS AND METHODS: The study included 32 patients with hormone refractory prostate cancer. Prior chemotherapy was accepted. Patients were treated with 100 mg./m.2 paclitaxel intravenously weekly, 10 mg./kg. estramustine phosphate orally daily and carboplatin intravenously to an area under the curve of 6 on day 1 of every 4-week cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: Of the 32 patients 30 were assessable for response. A median of 7 consecutive cycles was administered per patient. Ten patients had received prior cytotoxic chemotherapy. Levels of prostate specific antigen decreased by greater than 50% in 100% of patients and by greater than 90% in 56.7%. Partial response was obtained in 61.1% of measurable lesions. Consumption of medication for cancer induced pain was reduced in 89.5% of patients. Tumor volume reduction and/or antitumor therapeutic effects were exhibited in 81.0% of patients with positive biopsy. At a median followup of 48 weeks median time to progression was 48 weeks and median overall survival was 95 weeks. Two patients suffered myocardial infarction and hepatic insufficiency, respectively, and discontinued treatment during the first cycle. Major toxicities were grade 3 or 4 anemia in 59.4% of patients, leukopenia in 37.5%, thrombocytopenia in 28.1% and neuropathy in 12.5%. However, all toxicity was temporary and reversible with dose reduction or temporary cessation of chemotherapeutic agents. CONCLUSIONS: Paclitaxel, estramustine phosphate and carboplatin chemotherapy was extremely effective for hormone refractory prostate cancer. Although hematological and neurotoxicity were modest, this therapy may be more manageable with lower doses.     

Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy

OBJECTIVE: To evaluate the relationship between neuroendocrine differentiation (NED) status and hormone refractory prostate cancer (HRPC) following hormone therapy based on immunohistochemical study. METHODS: Seventy-two prostate cancer specimens obtained at radical prostatectomy and 21 prostate cancer autopsy specimens from patients who died from HRPC after androgen deprivation therapy were examined for NED status using an antibody against chromogranin A. These specimens were classified into 3 arms: 38 radical prostatectomy specimens from patients with no neoadjuvant hormone therapy (Group 1); 34 from patients with neoadjuvant hormone therapy for 3 to 6 months (Group 2); and 21 autopsy specimens from patients with HRPC following androgen deprivation therapy for more than 1 year (Group 3). Staining of prostatic carcinoma was scored as: 0 = no staining; 1 = staining cells <10%; 2 = staining cells 10-20%; and 3 = staining cells >20%. Differences in scores among the groups were compared using the Kruskal-Wallis rank test. Multivariate analysis using a logistic regression model was performed to examine whether NED status was associated with pathological stage (pT), grade and group. RESULTS: Forty-nine (53%) tumors had CgA stained cells. NED status increased with longer duration of hormone therapy (p<0.0001). The mean staining score (and standard deviation) was 0.4+/-0.7 in Group 1, 0.7+/-0.7 in Group 2, and 1.4+/-1.1 in Group 3, respectively. By multivariate analysis Group 3 had a relative risk of 5.46 (95%CI 1.28-23.29) for NED compared to the other groups. But other variables were not related to NED. HRPC following Long-term hormonal therapy was the only independent predictor of NED. CONCLUSIONS: The results of this study demonstrated that NED status was significantly increased in patients with HRPC following long-term androgen deprivation therapy, but it could not be discriminate whether the increase of NED is attributable to condition of hormone refractoriness or long-term hormonal therapy.     

Renin-angiotensin system is an important factor in hormone refractory prostate cancer

BACKGROUND: The aim of this study was to perform a comprehensive evaluation of the renin-angiotensin system (RAS) in prostate cancer. METHODS: We investigated the expression of RAS components in prostate cancer cells treated with hormonal agents. Real-time PCR data showed the expression of the AT1 receptor, angiotensin I converting enzyme (ACE), and angiotensin I/II (Ang-I/II) precursor in all 87 prostate tissue samples. RESULTS: Expression of these genes in hormone refractory prostate cancer (HRPC) was significantly higher than that in normal prostate tissue and untreated prostate cancer tissue. Western blot showed that protein expression of the AT1 receptor and Ang-I/II was enhanced in LNCaP cells cultivated in steroid-free medium. When LNCaP cells were stimulated with dihydrotestosterone (DHT), estradiol (E2), dexamethasone (DEX), or anti-androgen drugs, protein expression of the AT1 receptor and Ang-I/II was augmented. CONCLUSIONS: The present data suggest that prostatic RAS is overexpressed in HRPC tissue, and expression of its components is influenced by several kinds of hormonal stimulation.